Niemann-Pick type C (NPC) disease is a progressive neurological disorder of children characterized by dementia, ataxia, and death typically within the first or second decade. Despite the identification of over 300 causative mutations, therapies to successfully treat NPC disease have been ineffective to date. 2- hydroxypropyl-ss-cyclodextrin (HPssCD), an FDA-designated orphan drug (May 2010), is now being administered to a small number of children with NPC disease based on favorable treatment outcome data in subcutaneously treated npc1-/- mice and cats. However, due to the small patient sample size and the inability to undertake control studies in normal children for ethical reasons, the mechanisms of drug action and potential toxicity cannot be addressed in human patients. We propose to rigorously evaluate the pharmacologic, mechanistic, and toxicity issues in the feline model which has a spontaneously-occurring missense mutation in NPC1 (2864G-C) orthologous to the most common mutation in the most common form of NPC disease in patients and disease progression which recapitulates the neuropathological and biochemical abnormalities observed in these patients. Using the feline model, we achieved highly encouraging results following intrathecal HPssCD administration in that clinical neurological signs of disease were completely resolved at least up to 24 weeks of age (an age when untreated cats die), however, we identified a completely unanticipated dose-related toxic effect on the auditory system. We will utilize our highly innovative feline model to further evaluate disease pathogenesis and the therapeutic efficacy of HPssCD via the following aims: Specific Aim 1. Determine whether the CSF concentration of HPssCD predicts amelioration of NPC-related neurological disease and produces ototoxicity. Specific Aim 2. Identify sensitive and predictive biomarkers of neurological disease to monitor disease progression and treatment efficacy and provide insight into pathogenesis. Specific Aim 3. Evaluate non-invasive nuclear magnetic resonance (NMR) measures of brain disease progression and treatment efficacy. PUBLIC HEALTH RELEVANCE: In order to ultimately develop efficacious and safe compounds for therapy of NPC disease, the pharmacology, mechanism of action, and toxicity of experimental drug therapy must be understood and is possible using this model system. The paucity of validated surrogate markers of brain disease which could be monitored as secondary clinical endpoints presents a major obstacle in clinical trials in NPC disease, and the studies proposed will validate both biochemical and imaging markers of disease severity and therapeutic outcome in the feline model of NPC disease using techniques which are applicable to affected children.